In a post-hoc analysis of data from a combined phase I/II and IIa study, ALS patients who had NTF-producing mesenchymal stem cells delivered intrathecally had slowed disease progression when comparing scores on forced vital capacity and ALS Functional Rating Scale -- Revised (ALS-FRS-R) before and after transplant, reported Dimitrios Karussis, MD, PhD, of Hadassah Medical Center in Jerusalem, and colleagues in JAMA Neurology.

"To our knowledge, this is the first human experience with stem cells that have been induced under culture conditions to produce NTFs, thus bearing the potential to support neuronal survival and to modify the course of neurodegeneration in ALS," they wrote.

Preclinical studies have suggested that NTFs can extend survival of motor neurons in ALS, although giving single NTFs hasn't revealed any benefit.

A more effective approach might be direct delivery of multiple NTFs to the central nervous system (CNS), in this case through transplantation of cells that actively secrete these factors.

To determine the safety and possible efficacy of autologous transplant of mesenchymal stem cells induced to produce NTFs in patients with ALS, the researchers conducted a pair of open-label, proof-of-concept studies: one phase I/II, and the other a phase IIa study.

Patients with ALS were enrolled from June 2011 to October 2014 at Hadassah Medical Center in Jerusalem. In the phase I/II study, six patients with early ALS were given intramuscular injection of the stem cells, and six patients with more advanced disease were transplanted intrathecally.

In the phase IIa dose-escalating study, 14 patients with early-stage ALS received a combination of intramuscular and intrathecal transplantation of the autologous NTF-secreting stem cells.

All patients were followed for 3 months before transplant and 6 months after.

Karussis and colleagues found that the therapy was safe and well tolerated in both study phases. Most of the effects were mild and transient, and included headache, fever, vomiting, leg and back pain, and neck stiffness. There were no treatment-related serious adverse events.

In the phase I/II study, they saw improvement in the mean monthly rate of progression in terms of forced vital capacity and ALS-FRS-R in the intrathecal group, but not in the intramuscular group.

In the phase IIa study, they saw a more substantial improvement in the monthly rate of decline of ALS-FRS score and forced vital capacity in the months after stem cell transplant.

Given that only those who received intrathecal stem cells appeared to benefit, the researchers performed a post-hoc comparison between progression rate of ALS-FRS-R scores and forced vital capacity before and after treatment.

The rate of progression of the forced vital capacity was reduced (-5.1% to -1.2%/month percentage predicted forced vital capacity, P<0.04) as was the FRS-R score progression (-1.2 to 0.6 points per month, P=0.052) in the 6 months after transplant compared with the 3 months prior.

They also found that 87% of these patients were defined as responders, having at least 25% improvement in the slope of progression for either ALS-FRS-R or forced vital capacity 6 months after treatment.

"Although our study was primarily targeted to assess safety and not powered for efficacy, the data also provided some indications of clinically meaningful beneficial effects induced by the intrathecal treatment with [NTF-producing] mesenchymal stem cells," they wrote.

The study was limited by the small number of patients that were included, and by a lack of a placebo group, but an ongoing double-blind, placebo-controlled, multi-center phase II trial will yield more details, the researchers said.

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